The GNAO1 gene codes for the most commonly expressed Gα protein in the central nervous system. De novo GNAO1 variants cause complex early-onset neurological phenotypes, sometimes with distinct epilepsy or movement disorder manifestations, and sometimes with both manifestations in the same patient. G-protein coupled receptor (GPCR) signaling is among the best studied molecular interaction pathways in the human organism, which provides the input needed to quantitatively evaluate how mutations modify the GPCR signal. This in turn allows rational interpretation of distinct phenotypes arising from mutations in GNAO1. In this work we outline a model that enables understanding of clinical phenotypes at a molecular level and anticipating symptoms and treatment response for future patients. We show that apparently similar mutations in GNAO1 can lead to distinct phenotypes through distinct modulation of the incoming GPCR signal. Specifically, the epileptic phenotype arises necessarily in mutations affecting the catalytic pocket. Cases with movement disorders separate into two groups, responsive or nonresponsive to dopamine, corresponding, respectively, to the interfaces with GPCR and GNAO1s downstream effector. Mutations placed very close to either of these two interfaces may manifest as a movement disorder phenotype without epilepsy. In addition to the practical implications for decision making process in choosing therapy for GNAO1 patients, this system provides a precision medicine paradigm in which individual genomic information and understanding of the implications of variants at the molecular level can inform and guide the treatment process.

Molecular map of GNAO1-related disease phenotypes and reactions to treatment